Nitrous oxide medical air liquide

Package leaflet: Information for the patient

Nitrous Oxide Medical Air Liquide, 100%, liquefied medical gas
Dinitrogenii oxidum
Please read this leaflet carefully before using the medicine, as it contains important information for the patient.

• Keep this leaflet so that you can read it again if necessary.
• If you have any doubts, please consult your doctor or pharmacist.
• This medicine may harm another person, even if their symptoms are the same.
• If you experience any adverse reactions, including any not listed in this leaflet, inform your doctor or pharmacist. See section 4.

Table of contents:

1. What is Nitrous Oxide Medical Air Liquide and what is it used for
2. Important information before using Nitrous Oxide Medical Air Liquide
3. How to use Nitrous Oxide Medical Air Liquide
4. Possible side effects
5. How to store Nitrous Oxide Medical Air Liquide
6. Contents of the pack and other information

1. What is Nitrous Oxide Medical Air Liquide and what is it used for

Nitrous Oxide Medical Air Liquide belongs to the group of general anaesthetic medicines (nervous system and central nervous system) and is an inhaled gas.
This medicine is intended exclusively for use in hospitals.
This medicine is indicated in the following cases:

• as an adjunct to general anaesthesia, in combination with other anaesthetic agents administered intravenously or by inhalation.
• as an analgesic adjunct in superficial anaesthesia without loss of consciousness during short, painful procedures, e.g. after an accident, in burns, dental procedures, childbirth, and otolaryngological surgery (ear-related).

2. Important information before using Nitrous Oxide Medical Air Liquide

When not to use Nitrous Oxide Medical Air Liquide:

• if the patient requires ventilation with 100% oxygen.
• under any conditions where air is trapped within the body and its expansion could pose a risk, for example in cases of: head injuries, maxillofacial injuries, pneumothorax, gas embolism, decompression sickness, patients who have recently dived, patients who have undergone air encephalography, presence of bullous emphysema, during middle ear, inner ear or sinus surgery, significant abdominal distension (e.g. intestinal obstruction), when air has been injected into the epidural space to determine needle position during epidural anaesthesia.
• patients who have recently undergone intravitreal injection of gas (such as SF* hexafluoride, C*F* - octafluoropropane, C*F* - hexafluoroethane), until the gas bubble has resolved within the eyeball or for a period of 3 months after the last intravitreal gas injection. Expansion of the intraocular gas bubble due to nitrous oxide may cause serious visual damage.
• should not be used for longer than 24 hours.
• in case of any change in consciousness impairing cooperation with the patient during administration of nitrous oxide for pain relief.

Warnings and precautions

• nitrous oxide must always be administered with at least 21% oxygen.
• nitrous oxide causes inactivation of vitamin B*, thereby affecting folate metabolism. As a result, DNA synthesis may be impaired during prolonged administration of nitrous oxide. Frequent or prolonged use of nitrous oxide may lead to megaloblastic changes in bone marrow cells (impaired production of red blood cells), and possibly myeloneuropathy (spinal cord and peripheral nerve disease) and subacute combined degeneration of the spinal cord (spinal cord disease) (see also section 4).
• neurological toxicity after single exposure to nitrous oxide has been observed in patients with undiagnosed asymptomatic vitamin B* deficiency during general anaesthesia.
• prior to using nitrous oxide for anaesthesia in individuals with risk factors for vitamin B* deficiency, vitamin B* levels should be assessed. Risk factors may include alcohol dependence, patients suffering from anaemia (deficiency of red blood cells) or atrophic gastritis, individuals on a vegetarian diet. Other risk factors include pernicious anaemia, gastric cancer, post-gastrectomy state (total or partial removal of the stomach), intestinal diseases, malabsorption disorders, long-term use of proton pump inhibitors (medications that neutralize gastric acid), and others. In appropriate cases, especially with prolonged and repeated use of nitrous oxide, administration of vitamin B* to the patient is necessary.

When nitrous oxide is used for pain relief:

• Self-administration is preferred to allow assessment of the level of consciousness.
• Close monitoring is required for patients concurrently receiving medications that depress central nervous system function, especially opioids and benzodiazepines, due to increased risk of profound sedation.
• nitrous oxide is an oxidizing gas that supports and accelerates combustion.
• particular caution is required in patients with heart failure; if administration of nitrous oxide leads to hypotension (low blood pressure) or cardiac failure (the heart is unable to pump sufficient blood to the body), gas administration must be stopped immediately.
• special caution is required in patients who have undergone sinus or middle ear surgery.
• rooms where N*O is used must be equipped with an appropriate gas evacuation or ventilation system to maintain nitrogen concentration at the lowest possible level and below established national occupational exposure limits. In case of Eustachian tube obstruction, increased pressure in the middle ear cavity may result in ear pain and/or middle ear disorders and/or tympanic membrane rupture.

Children and adolescents
Nitrous oxide may rarely cause respiratory depression in newborns.
The newborn should be evaluated for possible respiratory depression if nitrous oxide was administered during the perinatal period.

Nitrous Oxide Medical Air Liquide and other medicines
Inform the physician about all medications currently used, recently used, or planned for use by the patient.
In appropriate cases, especially with prolonged and repeated administration of nitrous oxide, vitamin B* supplementation is necessary (see "Warnings and precautions" above and section 4).
Medications that interfere with vitamin B* and/or folic acid metabolism may enhance the inactivation of vitamin B* by nitrous oxide.
Patients who have recently undergone intravitreal gas injection (such as SF* - sulfur hexafluoride, C*F* - octafluoropropane, C*F* - hexafluoroethane), until the intraocular gas bubble has resolved or for a period of 3 months after the last intravitreal gas injection. Expansion of the intraocular gas bubble under the influence of nitrous oxide may cause serious visual damage.
Nitrous oxide enhances the sedative effects (drowsiness, sleep disturbances) of anaesthetics that depress central nervous system function, administered intravenously or by inhalation (thiopental, benzodiazepines, morphine derivatives, halogenated anaesthetic agents, or other psychotropic drugs); therefore, the dose of these drugs should be reduced when co-administered.

Pregnancy and breastfeeding

If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning a pregnancy, she should consult a physician before using this medicine.

Pregnancy:
Extensive data from pregnant women exposed to single administration of nitrous oxide during the first trimester (over 1000 exposure outcomes) indicate no teratogenic toxicity. Furthermore, exposure to nitrous oxide during pregnancy is not directly associated with fetal or neonatal toxicity. Nitrous oxide may therefore be used during pregnancy when clinically indicated. If nitrous oxide is administered shortly before delivery, newborns should be monitored for potential adverse effects.

Pregnant women should receive nitrous oxide at a concentration not exceeding 50% in the inhaled mixture.

Fertility:
No relevant data available in humans.

Breastfeeding
It is unknown to what extent nitrous oxide passes into breast milk. After short-term use of nitrous oxide, considering its very short half-life, interruption of breastfeeding is not necessary.

Driving and operating machinery
After discontinuation of nitrous oxide administration, especially following prolonged use, outpatients required to drive vehicles or operate machinery should remain under medical supervision until they regain the same level of alertness as before drug administration.

3. How to use Podtlenek Azotu Medyczny Air Liquide

Podtlenek Azotu Medyczny Air Liquide must only be administered in hospitals by qualified medical personnel, in accordance with the physician's instructions. If in doubt, consult a physician.
Nitrous oxide must only be administered during surgical procedures or in the delivery room, after mixing it with oxygen.
The physician will determine the appropriate dose of nitrous oxide, which will be administered in a suitable manner depending on the patient's needs, ensuring an adequate supply of oxygen to the patient's body.
Administration of a higher than recommended dose of Podtlenek Azotu Medyczny Air Liquide

• During analgesic use, overdose may result in dizziness, loss of consciousness, cyanosis, and death due to insufficient oxygen. In such a case, the physician will immediately discontinue nitrous oxide administration and take appropriate measures.
• In the case of overdose during general anesthesia (inhalation of nitrous oxide at concentrations above 70%), symptoms of hypoxia may occur. In such a situation, the inhaled fraction of nitrous oxide should be reduced, and the anesthesiologist should take actions as appropriate to the clinical needs. If there are any further doubts regarding the use of the medicinal product, consult a physician.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everybody will experience them.

Main adverse reactions:
Regarding pain relief
Uncommon ( occurs no more frequently than in 1 out of 10 patients):
excessive sedation, stimulation, anxiety, hallucinations, dreams.

Frequency unknown (cannot be estimated from available data):
headache.

Common for applications in pain relief and general anaesthesia
Nitrous oxide diffuses into gas-filled spaces in the body faster than nitrogen diffuses out. Administration of nitrous oxide may cause expansion of body cavities containing non-vented gas.

Common ( occurs no more frequently than in 1 out of 10 patients):
nausea, vomiting.

Uncommon ( occurs no more frequently than in 1 out of 100 patients):
paraesthesia (tingling, numbness), induction of euphoria, psychodysleptic disorders unrelated to other anaesthetic agents.

Frequency unknown (cannot be estimated from available data):
dizziness, myelopathy (paresis, sensory loss), neuropathy (nerve damage – sensory disturbances), subacute combined degeneration of the spinal cord (a syndrome of neurological symptoms such as spastic paralysis, exaggerated deep tendon reflexes, positive Babinski sign, absence of certain deep reflexes, impaired superficial and deep sensation, disturbances in motor coordination), increased intracranial pressure, megaloblastic anaemia (reduction below normal levels of red blood cells due to vitamin B₁₂ deficiency), pancytopenia (a haematological disorder characterised by deficiency of all normal blood cellular components: erythrocytes, leukocytes and thrombocytes), observed in cases of predisposing factors (cobalamin deficiency, substance abuse), leukopenia or granulocytopenia (observed after significant and prolonged exposure to anti-tuberculosis therapy in the 1950s), serious visual impairment (caused by gas expansion within the eye), ear pain, middle ear disturbances, tympanic membrane rupture (in case of Eustachian tube obstruction), respiratory depression (reduced respiratory rate and tidal volume (in newborns when nitrous oxide was administered during labour and delivery)), vitamin B₁₂ deficiency, disorientation.

Generalised seizures of unknown frequency

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor, pharmacist or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw, tel.: 22 49-21-301, fax: 22 49-21-309, e-mail: [email protected].
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions contributes to greater knowledge about the safety of the medicine.

5. How to store Nitrous Oxide Medical Air Liquide

Keep the medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the packaging after EXP.
The expiry date refers to the last day of the specified month.
The following information should be taken into account during storage and transport of the medicine:

• Store in the original gas cylinder.
• The gas cylinder must be stored tightly closed and in an upright position.
• Do not transfer the gas from one gas cylinder to another.
• Gas cylinders must be stored in well-ventilated or airy rooms or in ventilated external storage areas, protected from rain and direct sunlight.
• Cylinders must be protected from shock, falling, oxidizing and flammable substances, moisture, and sources of heat or ignition.

Storage of gas cylinders in storage:

• Cylinders must be stored in a ventilated or airy location, protected from adverse weather conditions and frost, clean, free from flammable materials, designated exclusively for the storage of medical gases, and secured with a lock.

Storage of gas cylinders during use:

• Before use, cylinders should be stored with the valve closed; avoid storing large numbers of cylinders.

6. Contents of the pack and other information

What Podtlenek Azotu Medyczny Air Liquide contains

• The active substance is nitrous oxide (liquefied gas under pressure at 44 bar at 15 ºC).
• The medicinal product contains no other ingredients.

What Podtlenek Azotu Medyczny Air Liquide looks like and contents of the pack
Podtlenek Azotu Medyczny Air Liquide is packaged in cylinders available in the following sizes:

• A 3 l cylinder containing 2.25 kg, delivering 1.22 m³ of gas at 1 bar pressure and 15 ºC,
• A 10 l cylinder containing 7.5 kg, delivering 4.06 m³ of gas at 1 bar pressure and 15 ºC,
• A 13.33 l cylinder containing 10 kg, delivering 5.41 m³ of gas at 1 bar pressure and 15 ºC,
• A 40 l cylinder containing 30 kg, delivering 16.23 m³ of gas at 1 bar pressure and 15 ºC,
• A 53.33 l cylinder containing 40 kg, delivering 21.65 m³ of gas at 1 bar pressure and 15 ºC,
• A bundle of 12 cylinders of 53.33 l capacity containing 480 kg, delivering 259.8 m³ of gas at 1 bar pressure and 15 ºC.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Air Liquide Santé International
75 quai d’Orsay
75007 Paris
France

Manufacturer:
Air Liquide Medical
Tolhuisstraat 46
2627 Schelle
Belgium

24 April 2019

Information intended exclusively for healthcare professionals:

Please refer to the Product Information available on the website of the
Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
( www.urpl.gov.pl ).
Dosage and administration

Nitrous oxide may be administered only in an operating theatre or in a delivery room.
(Outside operating and delivery rooms, if nitrous oxide is to be used for analgesia,
a ready-made equimolar mixture of nitrous oxide and oxygen 50%/50% should be used.)

According to existing regulations, administration of the medicinal product requires:
nitrous oxide – a nitrous oxide and oxygen blender must be used, which always ensures
oxygen concentration (FiO₂) greater than or equal to 21%, with the possibility of achieving
oxygen concentration (FiO₂) up to 100%, equipped with a check valve and an alarm system
that operates in case of failure in oxygen supply.
In the case of artificial ventilation, oxygen concentration (FiO₂) in exhaled air should be monitored.

Dosage

Nitrous oxide should be administered by inhalation, mixed with oxygen, at a concentration between 50% and 70%.
In pregnant women, nitrous oxide may be administered only in case of absolute necessity and at a concentration not exceeding 50% (see section 4.6).
Nitrous oxide should not be administered for longer than 24 hours due to its toxic effect on the spinal cord (see section 4.8).

Special warnings and precautions for use

• Nitrous oxide must always be administered with at least 21% oxygen.
• Nitrous oxide inactivates vitamin B₁₂ (a cofactor of methionine synthase), thereby affecting folate metabolism. As a result, DNA synthesis is impaired during prolonged administration of nitrous oxide. Frequent or prolonged use of nitrous oxide may cause megaloblastic changes in bone marrow cells and possibly myeloneuropathy and subacute combined degeneration of the spinal cord (see also section 4).
• Neurological toxicity after a single exposure to nitrous oxide has been observed in patients with undiagnosed subclinical vitamin B₁₂ deficiency during general anaesthesia.
• Prior to using nitrous oxide for anaesthesia in individuals with risk factors for vitamin B₁₂ deficiency, vitamin B₁₂ levels should be assessed. Risk factors may include alcohol dependence, patients suffering from anaemia or atrophic gastritis, individuals on a vegetarian diet. Other risk factors include pernicious anaemia, gastric cancer, post-gastrectomy status, intestinal diseases, malabsorption syndromes, long-term use of proton pump inhibitors, and others. In appropriate cases, especially during prolonged or repeated administration of nitrous oxide, supplementation with vitamin B₁₂ is necessary. When nitrous oxide is used for pain relief:
• Self-administration should be preferred to allow assessment of the level of consciousness.
• Careful monitoring is required in patients receiving concomitant medications that depress central nervous system function, especially opioids and benzodiazepines, due to increased risk of deep sedation.

Special warnings

Rooms where N₂O is used must be equipped with an appropriate gas scavenging or ventilation system to maintain nitrous oxide concentration at a minimal level and below established national occupational exposure limits.

In pregnant women occupationally exposed to chronic inhalation of nitrous oxide in rooms lacking an appropriate gas scavenging or ventilation system, an increased incidence of spontaneous abortions and fetal anomalies has been reported. These findings are questionable due to methodological flaws, exposure conditions, and the fact that no risk was observed in subsequent studies where appropriate gas scavenging or ventilation systems were used.

This gas is non-flammable but supports combustion of other materials, is heavier than air, and accumulates in low-lying areas. Nitrous oxide facilitates and accelerates combustion. The greatest ignition hazard in the presence of nitrous oxide involves flammable materials, particularly greasy substances (oils, greases) and organic materials (fabrics, wood, paper, plastics, etc.), which may ignite spontaneously or upon contact with a spark, flame, or ignition source.

Nitrous oxide may form explosive mixtures when combined with flammable gases or vapours used for anaesthesia, even in the absence of oxygen; it may also produce toxic nitrogen fumes in case of fire.

Administration of nitrous oxide may increase pressure in the cuffs of endotracheal tubes.
When introducing nitrous oxide into the breathing circuit, it may increase the concentration of halogenated anaesthetic agents (second gas effect), facilitating induction of anaesthesia.
Adding nitrous oxide to the circuit reduces the flow of halogenated anaesthetic vapours released during vaporization. Conversely, discontinuation of nitrous oxide increases the concentration of released halogenated agent. Therefore, it is recommended to discontinue the volatile halogenated anaesthetic agent before administering nitrous oxide.
During anaesthesia, diffusion hypoxia may occur in the first minutes after stopping nitrous oxide administration. During this period, oxygen concentration (FiO₂) in the inhaled air should be increased.
If unexpected cyanosis occurs during anaesthesia using a device supplied with nitrous oxide and oxygen, it is essential to first discontinue nitrous oxide administration; if cyanosis does not resolve rapidly, the patient should be ventilated manually using a resuscitator filled with ambient air.
In case of Eustachian tube obstruction, increased pressure in the middle ear cavity may result in ear pain and/or middle ear disorders and/or tympanic membrane rupture.
In patients at risk of increased intracranial pressure, intracranial pressure should be carefully monitored, as an increase in intracranial pressure has been observed in some patients with intracranial disorders during nitrous oxide administration.
Abuse, misuse, and off-label use: since nitrous oxide induces a state of euphoria, it may be used and abused recreationally.

Special precautions for use

Special precautions should be taken during administration of nitrous oxide:
in patients with heart failure; if hypotension or heart failure occurs during nitrous oxide administration, administration should be immediately discontinued.
after surgery on the sinuses or middle ear.

In pregnant women occupationally exposed to chronic inhalation of nitrous oxide in rooms lacking an appropriate gas scavenging or ventilation system, an increased incidence of spontaneous abortions and fetal anomalies has been reported. These findings are questionable due to methodological flaws, exposure conditions, and the fact that no risk was observed in subsequent studies where appropriate gas scavenging or ventilation systems were used.

Children and adolescents

Nitrous oxide rarely causes respiratory depression in newborns. The newborn should be evaluated for possible respiratory depression if nitrous oxide was administered during the peripartum period.

Special precautions for disposal and preparation of the medicinal product for use

Cylinders containing medical nitrous oxide are intended exclusively for hospital use.
Medical nitrous oxide should only be used in a mixture with medical oxygen.
Oxygen concentration in the breathing mixture (FiO₂) should not be lower than 30%.
To avoid potential accidents, the following instructions must be followed:
Cylinders must always be stored in an upright position to prevent the risk of liquid spray, which causes severe cryogenic burns (extremely low temperature).
In case of frostbite (cryogenic burns), rinse with large amounts of water.

• Cylinders supplied by the manufacturer must be equipped with safety systems ensuring they have not been tampered with.
• It should be noted that gas pressure inside the cylinder remains constant (44 bar at 15°C), regardless of the remaining liquid level, and does not reflect the amount of gas remaining in the cylinder. Only when the cylinder is empty does the pressure drop rapidly. Only the cylinder's weight allows calculation of its content during use.
• Before use, check the proper condition of the cylinder and valves.
• Do not handle any cylinder whose valve is not protected by a cap or protective cover.
• Handle cylinders with clean, grease-free hands.
• Wear protective gloves and safety footwear when handling cylinders.
• Secure cylinders with appropriate restraints (chains, hooks, etc.) to keep them upright and prevent falling.
• Never place a cylinder on a holder where it fits loosely.
• Never lift a cylinder by the valve.
• Use a special connection for nitrous oxide.
• Use a pressure regulator equipped with a flowmeter capable of withstanding pressure at least 1.5 times greater than the maximum working pressure in the cylinder.
• For cylinder manifolds, only pressure regulators calibrated for at least 315 bar should be used.
• Use flexible connections for wall outlets specifically designed for medical nitrous oxide.
• Do not use intermediate connectors allowing attachment of two incompatible devices.
• Open the valve gradually.
• Never use force to open the valve.
• Purge the outlet connection of the cylinder before attaching the pressure regulator to remove dust.
• Never stand directly in front of the valve outlet; always position yourself on the side opposite the pressure regulator, behind the cylinder, at a safe distance. Never expose the patient to the gas flow stream.
• Compatibility (conformity) of materials in contact with medical nitrous oxide must be verified beforehand, and in particular, sealing gaskets compatible with the pressure regulator for this gas should be used. Check the condition of gaskets regularly.

Do not smoke.
Keep away from fire.
Do not use greases.
In particular:
a) Never introduce gas into a device where flammable substances may be present, especially greasy substances,
b) Never clean gas containers, valves, gaskets, inserts, closing devices, or circuits with flammable products, especially greasy substances,

• Do not apply greasy substances (vaseline, ointments, etc.) to patients' faces,
• Do not use aerosol generators (hair sprays, deodorants, etc.) or solvents (alcohol, gasoline, etc.) on cylinders or in their vicinity,
• After use, close the cylinder valve, allow the pressure regulator to depressurize while leaving the flowmeter open, close the flowmeter, then loosen the pressure regulator adjusting screw.

Do not attempt to repair a damaged valve.

In case of gas leakage, close the damaged supply valve immediately. Ventilate the room quickly and evacuate people. Without oxygen supply, it causes asphyxiation in humans.
Nitrous oxide is a colorless, odorless gas, heavier than air, accumulating in low-lying spaces.
Never use cylinders showing signs of leakage; check operation of the spare cylinder.
If, after opening the valve, the flow is high and frost forms on the pressure regulator, do not use the cylinder and return it to the pharmacy.

• When ambient temperature is low or during high usage causing cylinder cooling, gas flow may decrease or even stop due to insufficient pressure in the cylinder.
• Avoid using the cylinder at temperatures below 0°C to prevent pressure drop during intensive use.
• Never use medical nitrous oxide for leak testing, powering pneumatic devices, or purging pipes.
• The average occupational exposure limit (over 8 hours) for nitrous oxide is set at 25 ppm for personnel.
• Ensure systematic ventilation (aeration) of the area where nitrous oxide is used, directing gases outdoors and avoiding locations where gases could accumulate. Before each use, confirm the ability to remove gases in case of accidental or premature leakage.
• If cylinder pressure drops significantly (to about 3–5 bar), consider it empty, close the valve (to prevent moisture-induced corrosion), and disconnect the equipment. Maintain residual pressure in the cylinder to prevent contamination.
• Empty and full cylinders must be stored separately.
• Empty cylinders must be stored upright with the valve closed to prevent moisture-induced corrosion.

Transport of gas cylinders:
Cylinders must be transported in an upright position and secured using appropriate devices (such as a trolley equipped with chains, barriers, or rings) to protect against shocks and falls, thus preventing cryogenic burns in case the valve opens accidentally.
Particular care must be taken when connecting the pressure regulator valve to avoid accidental damage.